# NM_001367721.1(CASK):c.1837C>T (p.Arg613Ter)

https://sugi.bio/variant/cask-p-arg613ter

## Summary

**CASK p.Arg613Ter (c.1837C>T)** is classified **Pathogenic/Likely pathogenic** in CASK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-07-14). Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs779508996 · 7 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CASK gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to syndromic X-linked intellectual disability Najm type.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CASK is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of X-linked intellectual disability, Najm type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive microcephaly — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Intellectual disability, moderate — Very frequent (99-80%)
- Severe global developmental delay — Very frequent (99-80%)
- Hypoplasia of the pons — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Retrognathia — Frequent (79-30%)
- Hypertelorism — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012669/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CASK](https://sugi.bio/atlas/gene/CASK/) |
| Protein change (HGVS p.) | p.Arg613Ter |
| Coding change (HGVS c.) | c.1837C>T |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| dbSNP | [rs779508996](https://www.ncbi.nlm.nih.gov/snp/rs779508996/) |
| Variant type | single nucleotide variant |
| Location | chrX:41555605-41555605 (GRCh38) |
| ClinVar | [VCV418109](https://www.ncbi.nlm.nih.gov/clinvar/variation/418109/) |

**All HGVS expressions:** `NC_000023.10:g.41414858G>A`, `NC_000023.11:g.41555605G>A`, `NG_016754.2:g.372430C>T`, `NM_001126054.3:c.1768C>T`, `NM_001126055.3:c.1750C>T`, `NM_001367721.1:c.1837C>T`, `NM_001410745.1:c.1819C>T`, `NM_003688.4:c.1837C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.684, GERP 1.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 20 of 27**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.22 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **X-linked syndromic intellectual disability** — Definitive (XL)

## Protein context {#protein}

Residue **613** lies in a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region.

AlphaFold model confidence (whole protein): pLDDT 79.45, 46% of residues very-high.

**22 experimental structure(s)** (PDB): [1KGD](https://www.rcsb.org/structure/1KGD), [1KWA](https://www.rcsb.org/structure/1KWA), [1ZL8](https://www.rcsb.org/structure/1ZL8), [3C0G](https://www.rcsb.org/structure/3C0G), [3C0H](https://www.rcsb.org/structure/3C0H), [3C0I](https://www.rcsb.org/structure/3C0I).

## What this gene does {#gene-function}

*Describes the biological roles of CASK (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CASK's established molecular role includes protein serine/threonine kinase activity. p.Arg613Ter falls in the sh3 domain.


### Pathways affected {#pathways}

CASK participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dopamine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-212676) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |
| [Syndecan interactions](https://reactome.org/content/detail/R-HSA-3000170) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity.

**Biological process:** negative regulation of cell-matrix adhesion, negative regulation of keratinocyte proliferation, negative regulation of wound healing, negative regulation of cellular response to growth factor stimulus.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-14.

**Submitter consensus:** conflicting (5 Pathogenic, 2 Likely pathogenic).

**Submission history:** 7 submissions (2002–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-10 |
| Center of Genomic medicine, Geneva, University Hospital of Geneva | Pathogenic | criteria provided, single submitter | clinical testing | 2016-11-14 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2019-02-28 |
| Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-06-09 |
| Center of Excellence for Medical Genomics, Chulalongkorn University | Likely pathogenic | no assertion criteria provided | research | 2002-09-08 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-24 |

## Associated conditions {#conditions}

[syndromic X-linked intellectual disability Najm type](https://sugi.bio/atlas/disease/syndromic-x-linked-intellectual-disability-najm-type/), [FG syndrome 4](https://sugi.bio/atlas/disease/fg-syndrome-4/).

**Reported phenotype names (ClinVar):** Syndromic X-linked intellectual disability Najm type, not provided, FG syndrome 4, Intellectual disability, CASK-related, X-linked, none provided, Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, MENTAL RETARDATION, X-LINKED, SYNDROMIC, NAJM TYPE, Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH), Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia.

## Same-residue context {#hotspot}

Residue **613** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CASK p.Arg613fs](/variant/cask-p-arg613fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [CASK p.Arg613fs](/variant/cask-p-arg613fs), [CASK p.Arg613Gln](/variant/cask-p-arg613gln), [CASK c.1015+1G>A](/variant/cask-c-1015-plus-1g-a), [CASK c.1315-1G>A](/variant/cask-c-1315-minus-1g-a), [CASK c.2317+1G>A](/variant/cask-c-2317-plus-1g-a), [CASK c.2317+5G>A](/variant/cask-c-2317-plus-5g-a), [CASK c.2521-2A>G](/variant/cask-c-2521-minus-2a-g), [CASK c.59+2T>C](/variant/cask-c-59-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 418109). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*